Progesterone is essential for the normal morphologic development of the luteal phase endometrium for implantation of a blastocyst and for maintenance of Pregnancy. Surprisingly, given its critical role in reproduction, little is known about the mediator(s) of progesterone action. We are using a recently described progestin-dependent glycoprotein, placental protein 14 (PP14) and the antiprogestin RU 486 to probe progesterone action. We are investigating the relationship between endogenous progesterone production, serum PP14 concentrations and endometrial maturation in women with normal cycles and those with luteal phase defects. We are also examining the secretion of PP14 by endometrial explants obtained from normal women, those with idiopathic infertility and those with habitual abortion. These studies suggest that serum PP14 concentrations and direct examination of endometrial secretion of PP14 may be better indicators of uterine function than those currently employed. Further studies in infertile women and those with multiple miscarriages may give better insight into the cause, and possibly, the treatment of these disorders. Guinea pigs, like women, require progesterone for normal endometrial development, implantation and pregnancy. We have used the antiprogestin RU 486 to probe the process of implantation in this animal model. Small daily doses of the drug result in a marked decrease in implantation sites, confirming the critical role of progesterone in nidation. Studies in non-pregnant women show that small daily doses of RU 486 delay the normal maturation of the endometrium without significantly changing the hormonal patterns or timing of the menstrual cycle. Serum PP14 concentrations were significantly decreased in the women receiving RU 486, showing that progesterone (and not some other product of the corpus luteum) is critical for normal endometrial morphology. No adverse effects were seen in either study. Taken together, these data suggest that RU 486 has potential as a contraceptive agent.